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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 390-396. doi: 10.19723/j.issn.1671-167X.2019.03.003

• 工作综述 • 上一篇    下一篇

激活毒蕈碱乙酰胆碱受体调控下颌下腺分泌的机制研究

丛馨1,2,闵赛南3,吴立玲1,2,蔡志刚3,俞光岩3△()   

  1. 1. 北京大学口腔医学院·口腔医院,唾液腺疾病研究中心,　国家口腔疾病临床医学研究中心　口腔数字化医疗技术和材料国家工程实验室　口腔数字医学北京市重点实验室,北京　100081
    2. 京大学基础医学院生理学与病理生理学系,北京　100191
    3. 北京大学口腔医学院·口腔医院口腔颌面外科,北京 100081
  • 收稿日期:2019-03-31 出版日期:2019-06-18 发布日期:2019-06-26
  • 作者简介:俞光岩,北京大学口腔医院口腔颌面外科教授、博士生导师,中华口腔医学会会长。主要研究方向为唾液腺疾病、口腔颌面部肿瘤以及唾液腺移植治疗重症干眼症。先后承担国家及省部级科研基金项目40余项,培养研究生及博士后80余名。率先开展腮腺功能性外科,明显减少手术并发症;提出唾液腺肿瘤临床病理新特点,牵头制定《唾液腺肿瘤诊断和治疗指南》;利用多学科交叉优势,创建了下颌下腺移植治疗重症干眼的关键技术体系并推广应用;完成了全世界病例数最多的下颌下腺移植治疗重症干眼的临床和基础研究;提出激活辣椒素受体调控下颌下腺分泌的新机制以及以受体为靶点人工调控移植下颌下腺分泌的新策略,创立了部分下颌下腺移植预防术后泪溢的新术式和诊治慢性阻塞性移植下颌下腺炎的新技术,明显提高了临床疗效;主持制定了《血管化自体下颌下腺移植治疗重症干眼症的指南》;开展下颌下腺功能保存治疗的系列研究,国内率先开展下颌下腺转位预防放射性口干新术式;建立腮腺和下颌下腺CT体积测量新方法,为腮腺和下颌下腺肿大的诊断提供客观标准;揭示IgG4相关唾液腺炎的临床、病理和影像学特点,建立IgG4相关唾液腺炎的诊断和治疗体系。先后发表SCI论文150余篇,以第一完成人获国家科学技术进步奖二等奖1项、省部级科技进步奖一等奖3项,获“全国五一劳动奖章获得者”“全国卫生系统先进工作者”“全国优秀科技工作者”等称号,并被中国香港牙医师学院、英国爱丁堡皇家外科医师学院和英国英格兰皇家外科医师学院先后授予“Honorary Fellowship”。
  • 基金资助:
    国家自然科学基金(81671005、81771093)

Role and mechanism of muscarinic acetylcholine receptor in the regulation of submandibular gland secretion

Xin CONG1,2,Sai-nan MIN3,Li-ling WU1,2,Zhi-gang CAI3,Guang-yan YU3△()   

  1. 1. Center for Salivary Gland Diseases, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China
    3. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2019-03-31 Online:2019-06-18 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China(81671005、81771093)

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关键词: 毒蕈碱乙酰胆碱受体, 下颌下腺, 分泌, 水通道蛋白, 紧密连接

Abstract:

SUMMARY Muscarinic acetylcholine receptors (mAChRs), including M1-M5 subtypes, are classic receptors in regulating water, ion, and solute transport in salivary gland. Our work focuses on the studies on the expression pattern and function of mAChR in the submandibular gland (SMG), and the under-lying mechanism involved in the mAChR-regulated secretion, together with the effect of parasympathectomy on the salivary secretion. Microvascular autotransplantation of SMG into the temporal fossa provides a continuous and endogenous source of fluids, and is currently an effective method for treating severe keratoconjunctivitis sicca. By using RT-PCR, Western blotting, and immunofluorescence, our data demonstrated that the expression of M1 and M3 subtypes were decreased in latent period in rabbit SMG autotransplantation model, whereas carbachol stimulation promoted the salivary secretion, as well as M1 and M3 expressions. By contrast, mAChRs were hypersensitive in epiphora SMGs, whereas atropine gel and botulinum toxin A application significantly inhibited the hypersecretion in both animal models and patients. Furthermore, the possible intracellular signal molecules involved in the mAChR-modulated saliva-ry secretion were explored. Activation of mAChR upregulated the expression of aquaporin 5 (AQP5), the main transporter that mediated water secretion through transcellular pathway, and led to AQP5 trafficking from lipid rafts to non-lipid microdomain. Extracellular signal-regulated kinase 1/2 (ERK1/2) was involved in the mAChR-regulated AQP5 content. mAChR activation also modulated the expression, distribution, and function of tight junction proteins, and increased paracellular permeability. ERK1/2/β-arrestin2/clathrin/ubiquitin signaling pathway was responsible for the mAChR-regulated downregulation of tight junction molecule claudin-4. Cytoskeleton filamentous actin (F-actin) was also involved in the distribution and barrier function of epithelial tight junctions. Besides, endothelial tight junctions were opened by mAChR agonist-evoked salivation in the mice. Furthermore, parasympathetic denervation increased resting salivary secretion in the long terminrats and minipigs. Taken together, our work demonstrated that mAChR regulated saliva secretion via transcellular and paracellular pathways in SMG epithe-lium as well as tight junction opening in SMG endothelium. Modulation of mAChR might be a promising strategy to ameliorate SMG dysfunction.

Key words: Muscarinic acetylcholine receptor, Submandibular gland, Secretion, Aquaporin, Tight junction

中图分类号: 

  • R781.7

图1

激活毒蕈碱乙酰胆碱受体对下颌下腺上皮和内皮细胞物质转运的影响"

[1] Iwasaki M, Borgnakke WS, Yoshihara A , et al. Hyposalivation and 10-year all-cause mortality in an elderly Japanese population[J]. Gerodontology, 2018,35(2):87-94.
doi: 10.1111/ger.2018.35.issue-2
[2] Proctor GB, Carpenter GH . Regulation of salivary gland function by autonomic nerves[J]. Auton Neurosci, 2007,133(1):3-18.
doi: 10.1016/j.autneu.2006.10.006
[3] Wess J, Blin N, Mutschler E , et al. Muscarinic acetylcholine receptors: structural basis of ligand binding and G protein coupling[J]. Life Sci, 1995,56(11-12):915-922.
doi: 10.1016/0024-3205(95)00028-5
[4] Hulme EC, Birdsall NJ, Buckley NJ . Muscarinic receptor subtypes[J]. Annu Rev Pharmacol Toxicol, 1990,30:633-673.
doi: 10.1146/annurev.pa.30.040190.003221
[5] Wei J, Walton EA, Milici A , et al. m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC[J]. J Neurochem, 1994,63(3):815-821.
[6] Giraldo E, Martos F, Gomez A , et al. Characterization of muscarinic receptor subtypes in human tissues[J]. Life Sci, 1988,43(19):1507-1515.
doi: 10.1016/0024-3205(88)90398-0
[7] Ryberg AT, Warfvinge G, Axelsson L , et al. Expression of muscarinic receptor subtypes in salivary glands of rats, sheep and man[J]. Arch Oral Biol, 2008,53(1):66-74.
doi: 10.1016/j.archoralbio.2007.07.012
[8] Shi L, Cong X, Zhang Y , et al. Carbachol improves secretion in the early phase after rabbit submandibular gland transplantation[J]. Oral Dis, 2010,16(4):351-359.
doi: 10.1111/odi.2010.16.issue-4
[9] Matsui M, Motomura D, Karasawa H , et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype[J]. Proc Natl Acad Sci USA, 2000,97(17):9579-9584.
doi: 10.1073/pnas.97.17.9579
[10] Gautam D, Heard TS, Cui Y , et al. Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice[J]. Mol Pharmacol, 2004,66(2):260-267.
doi: 10.1124/mol.66.2.260
[11] Nakamura T, Matsui M, Uchida K , et al. M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice[J]. J Physiol, 2004,558(Pt 2):561-575.
doi: 10.1113/jphysiol.2004.064626
[12] Zhang L, Su JZ, Cai ZG , et al. Factors influencing the long-term results of autologous microvascular submandibular gland transplantation for severe dry eye disease[J]. Int J Oral Maxillofac Surg, 2019,48(1):40-47.
[13] Yu GY, Zhu ZH, Mao C , et al. Microvascular autologous submandibular gland transfer in severe cases of keratoconjunctivitis sicca[J]. Int J Oral Maxillofac Surg, 2004,33(3):235-239.
doi: 10.1006/ijom.2002.0438
[14] Su JZ, Cai ZG, Liu XJ , et al. Management of duct obstruction in transplanted submandibular glands[J]. J Craniomaxillofac Surg, 2018,46(5):825-830.
doi: 10.1016/j.jcms.2018.03.006
[15] Su JZ, Cai ZG, Yu GY . Microvascular autologous submandibular gland transplantation in severe cases of keratoconjunctivitis sicca[J]. Maxillofac Plast Reconstr Surg, 2015,37(1):5.
doi: 10.1186/s40902-015-0006-4
[16] Yang NY, Ding C, Li J , et al. Muscarinic acetylcholine receptor-mediated tight junction opening is involved in epiphora in late phase of submandibular gland transplantation[J]. J Mol Histol, 2017,48(2):99-111.
doi: 10.1007/s10735-016-9709-9
[17] Ding C, Cong X, Zhang Y , et al. Hypersensitive mAChRs are involved in the epiphora of transplanted glands[J]. J Dent Res, 2014,93(3):306-312.
doi: 10.1177/0022034513519107
[18] Liu XJ, Li M, Su JZ , et al. Carbachol improves the secretion of transplanted submandibular glands during the latent period after microvascular autologous transplantation for severe keratoconjunctivitis sicca[J]. Int J Oral Maxillofac Surg, 2016,45(10):1273-1279.
doi: 10.1016/j.ijom.2016.03.015
[19] Cai JR, Shan XF, Cai ZG , et al. A new treatment for epiphora secondary to submandibular gland transplantation: transcutaneous atropine gel[J]. Ocul Surf, 2014,12(3):221-226.
doi: 10.1016/j.jtos.2014.04.001
[20] Shan XF, Lv L, Cai ZG , et al. Botulinum toxin A treatment of epiphora secondary to autologous submandibular gland transplantation[J]. Int J Oral Maxillofac Surg, 2019,48(4):475-479.
doi: 10.1016/j.ijom.2018.07.003
[21] 俞光岩, 吴立玲, 蔡志刚 , 等. 血管化自体下颌下腺移植治疗重症干眼20年研究[J]. 北京大学学报(医学版), 2018,50(1):1-4.
[22] 血管化自体颌下腺移植治疗重症角结膜干燥症研究项目组. 血管化自体颌下腺移植治疗重症角结膜干燥症指南[J]. 中华口腔医学杂志, 2010,45(7):391-393.
[23] Kawedia JD, Nieman ML, Boivin GP , et al. Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex[J]. Proc Natl Acad Sci USA, 2007,104(9):3621-3626.
doi: 10.1073/pnas.0608384104
[24] Yoshimura S, Nakamura H, Horai Y , et al. Abnormal distribution of AQP5 in labial salivary glands is associated with poor saliva secretion in patients with Sjögren’s syndrome including neuromyelitis optica complicated patients[J]. Mod Rheumatol, 2016,26(3):384-390.
doi: 10.3109/14397595.2015.1083146
[25] Li Z, Zhao D, Gong B , et al. Decreased saliva secretion and down-regulation of AQP5 in submandibular gland in irradiated rats[J]. Radiat Res, 2006,165(6):678-687.
doi: 10.1667/RR3569.1
[26] Huang Y, Shi X, Mao Q , et al. Aquaporin 5 is degraded by autophagy in diabetic submandibular gland[J]. Sci China Life Sci, 2018,61(9):1049-1059.
doi: 10.1007/s11427-018-9318-8
[27] Xu H, Shan XF, Cong X , et al. Pre- and post-synaptic effects of botulinum toxin A on submandibular glands[J]. J Dent Res, 2015,94(10):1454-1462.
doi: 10.1177/0022034515590087
[28] Tsukita S, Tanaka H, Tamura A . The claudins: from tight junctions to biologicalsystems[J]. Trends Biochem Sci, 2019,44(2):141-152.
doi: 10.1016/j.tibs.2018.09.008
[29] 丛馨, 张艳, 俞光岩 , 等. 激活辣椒素受体是调控下颌下腺分泌的新途径[J]. 北京大学学报(医学版), 2015,47(1):8-12.
[30] Angelow S, Ahlstrom R, Yu AS . Biology of claudins[J]. Am J Physiol Renal Physiol, 2008,295(4):F867-F876.
doi: 10.1152/ajprenal.90264.2008
[31] Cong X, Zhang Y, Shi L , et al. Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland[J]. Lab Invest, 2012,92(5):753-768.
doi: 10.1038/labinvest.2012.12
[32] Zhang XM, Huang Y, Zhang K , et al. Expression patterns of tight junction proteins in porcine major salivary glands: a comparison study with human and murine glands[J]. J Anat, 2018,233(2):167-176.
doi: 10.1111/joa.2018.233.issue-2
[33] Cong X, Zhang Y, Li J , et al. Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells[J]. J Cell Sci, 2015,128(12):2271-2286.
doi: 10.1242/jcs.165878
[34] Ding C, Zhang Y, Peng X , et al. Proteomic analysis of human transplanted submandibular gland in patients with epiphora after transplantation[J]. J Proteome Res, 2011,10(5):2206-2215.
doi: 10.1021/pr100965q
[35] Ding C, Cong X, Zhang XM , et al. Decreased interaction between ZO-1 and occludin is involved in alteration of tight junctions in transplanted epiphora submandibular glands[J]. J Mol Histol, 2017,48(3):225-234.
doi: 10.1007/s10735-017-9716-5
[36] Cong X, Zhang Y, He QH , et al. Endothelial tight junctions are opened in cholinergic-evoked salivation in vivo[J]. J Dent Res, 2017,96(5):562-570.
doi: 10.1177/0022034516685048
[37] Cong X, Zhang XM, Zhang Y , et al. Disruption of endothelial barrier function is linked with hyposecretion and lymphocytic infiltration in salivary glands of Sjögren’s syndrome[J]. Biochim Biophys Acta Mol Basis Dis, 2018,1864(10):3154-3163.
doi: 10.1016/j.bbadis.2018.07.002
[38] Qi W, Cong X, Zhang XM , et al. Parasympathectomy increases resting salivary secretion in normal and irradiated submandibular glands of rats[J]. Eur J Oral Sci, 2017,125(2):110-118.
doi: 10.1111/eos.2017.125.issue-2
[39] Zhang XM, Huang Y, Cong X , et al. Parasympathectomy increases resting secretion of the submandibular gland in minipigs in the long term[J]. J Cell Physiol, 2019,234(6):9515-9524.
doi: 10.1002/jcp.v234.6
[40] Ferlay J, Soerjomataram I, Dikshit R , et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015,136(5):E359-E386.
doi: 10.1002/ijc.29210
[41] Jensen SB, Pedersen AM, Vissink A , et al. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life[J]. Support Care Cancer, 2010,18(8):1039-1060.
doi: 10.1007/s00520-010-0827-8
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ISSN 1671-167X
CN 11-4691/R
主管单位：中华人民共和国教育部
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